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Tumor Treating Fields (TTFields) induced cancer cell death may be immunogenic resulting in enhanced antitumor efficacy when combined with immune-modulating therapy
Moshe Giladi
Head of Preclinical Studies
Novocure Ltd.
Confidential - For internal training purposes only. Not to be distributed or used in the field
(C) 2016 Novocure. All rights reserved. Novocure is a trademark of Novocure. SRC-046
TTFields Distribution in and Around Quiescentand Dividing Cells
Oscillatingdirection of force acting on charge
Oscillatingdirection of force
Unidirectional net force acting on dipole during all
cycle phases
Unidirectional net force acting on
charge during all
A B
Kirson ED, Dbalý V, Tovarys F, et al. PNAS. 2007;104(24):10151-10157.
uniform electric field leading to dipoles alignment
nonuniform electric field leading to dielectrophoresis
direction of force acting on dipole
charge during all cycle phases
Field of alternating direction Field of alternating direction
Confidential - For internal training purposes only. Not to be distributed or used in the field
TTFields MOA Summary
Contractile ring
mislocalization
NSCLC
Ovarian
NSCLC
Modified from Giladi M, Schneiderman RS, Scientific Reports, 2015 and Gera et al., PLoS One. 2015
Confidential - For internal training purposes only. Not to be distributed or used in the field
Ovarian
Glioma
TTFields Are Delivered by Optune
• Single-use transducer arrays deliver TTFields through the scalp1
– Arrays deliver TTFields at a low intensity (1-3 V/cm) and intermediate
1. Optune Patient Information and Operation Manual. Novocure Inc. Document number QSD-QR-331. November 1, 2014. 2. Optune Instructions for Use. Novocure Inc. Document number QSD-QR-330. November 2014.
and intermediate frequency (200 kHz)2
Confidential - For internal training purposes only. Not to be distributed or used in the field
EF-14: Secondary Endpoint, OS1
Interim Analysis, Per Protocol Population
TMZ aloneTTFields + TMZ
4TTFields + TMZ
(n=196)TMZ Alone
(n=84)
Median OS from randomization, months1 20.5 15.6
95% CI, months1 16.6-24.9 12.9-18.5
Stratified log-rank1 P=0.0042
HR (95% CI)1 0.666 (0.495-0.898)
Median OS from diagnosis, months2 24.4 19.4
1.0
0.9
0.8
0.7
0.6
0.5
0.4
Fra
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on
Su
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Overall Survival (months)
months
2-year OS1 48% 32%
TMZ, temozolomide; CI, confidence interval; HR, hazard ratio; OS, overall survival.References: 1. Optune Instructions for Use. Novocure. Document number QSD-QR-330. 2015. 2. Novocure Data on File OPT-103.
• In the final analysis (n=609), TTFields + TMZ extended median OS by 4.4 months, consistent with the interim analysis (n=280)1
0.4
0.3
0.2
0.1
0.00 6 12 18 24 30 36 42 48 54 60
+ Censored
Fra
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Confidential - For internal training purposes only. Not to be distributed or used in the field
In Vivo Evidence of Immune Stimulation in Response to TTFields Application
Control TTFields
Kirson ED, Giladi M, Gurvich Z.et al. Clin Exp Met. 2009;26:633-640.
TT
Fie
lds
Contr
ol
Confidential - For internal training purposes only. Not to be distributed or used in the field
Immunogenic Cell Death - Sequential Events that Link Tumor-Cell Stress with Activation of Antigen-Presenting Cells
Calreticulin acts on the scavenger receptor
(Eat me signal)
Zitvogel et.al , Nature reviews Immunology 2008
Toll-like receptor 4 is responsible for
activating the innate immune system.
Confidential - For internal training purposes only. Not to be distributed or used in the field
TTFields Application Mediate Cell Surface Exposure of Calreticulin
LLC-1Mouse lung cancer
MOSE-L Mouse ovarian cancer
Confidential - For internal training purposes only. Not to be distributed or used in the field
Giladi et al., AAI 2016
TTFields Induce an Increase in HMGB1 Release and a Reduction in Intracellular ATP Levels
LLC-1Mouse lung cancer
Confidential - For internal training purposes only. Not to be distributed or used in the field
MOSE-L Mouse ovarian cancer
Giladi et al., AAI 2016
Sequential Events that Link Tumor-Cell Stress with Activation
of Antigen-Presenting Cells
TTFields
Confidential - For internal training purposes only. Not to be distributed or used in the field
Cancer Immunity Cycle
Anti-PD1Anti-PD-L1
TTFields
Image from Chen DS, et al. Immunity. 39:1-10. Copyright © 2013 Elsevier Inc.
Confidential - For internal training purposes only. Not to be distributed or used in the field
Assay design
Leukocyte fraction ofblood donation
acquired from MADA: ample supply of cells
from multiple donors (5)
PBMC production
&preservation
� CFSE staining to detect proliferation
� Activate cells with PHA Superantigen
Incubate in normal conditions / inovitro for 3.5 days
Stain to:� Isolate T-cells� Detect immune activity: � Cytokine Secretion � Cytotoxic Degranulation� Activation/ Exhaustion Marker
Flow cytometry analysis
Diamant et al., ISCR 2016
Confidential - For internal training purposes only. Not to be distributed or used in the field
• Results indicate activated T cells treated
with TTFields exhibit slight /no
decrease (sometimes even increase) in
IFNγ secretion, PD1 up-regulation, and
cD107a surface presentation.
CD4+
CD8+
Effect of TTFields on T-cell activation in PBMC culture
Live CD3+ T cells
CD8+
CD8-
CD4-
Diamant et al., ISCR 2016
Confidential - For internal training purposes only. Not to be distributed or used in the field
Cancer Immunity Cycle
Chen DS, et al. Immunity. 39:1-10, 2013.
?
Confidential - For internal training purposes only. Not to be distributed or used in the field
TTFields in Combination with Anti-PD-1 Lead to an Increase in
Antigen Presenting Cells Infiltration to the Tumor
Giladi et al., AAI 2016
Confidential - For internal training purposes only. Not to be distributed or used in the field
TTFields in Combination with Anti-PD-1 Lead to Elevated PD-L1 Expression
and Reduced Tumor Volume
Giladi et al., AAI 2016
Confidential - For internal training purposes only. Not to be distributed or used in the field
Summary of TTFields effects
• Disrupt normal mitotic spindle assembly leading to mitotic catastrophe
• Lead to abnormal chromosomal segregation
• Induce autophagy
• Activate immunogenic cell death
• Demonstrate enhanced antitumor efficacy when combined with immune-
modulating therapy
Confidential - For internal training purposes only. Not to be distributed or used in the field
Cancer Immunity Cycle
TTFields
Image from Chen DS, et al. Immunity. 39:1-10. Copyright © 2013 Elsevier Inc.
Confidential - For internal training purposes only. Not to be distributed or used in the field
Novocure preclinical studies
Confidential - For internal training purposes only. Not to be distributed or used in the field